2. Academic Validation
  3. Impaired Transferrin Receptor Palmitoylation and Recycling in Neurodegeneration with Brain Iron Accumulation

Impaired Transferrin Receptor Palmitoylation and Recycling in Neurodegeneration with Brain Iron Accumulation

  • Am J Hum Genet. 2018 Feb 1;102(2):266-277. doi: 10.1016/j.ajhg.2018.01.003.
Anthony Drecourt 1,  Joël Babdor 1,  Michael Dussiot 1,  Floriane Petit 2,  Nicolas Goudin 3,  Meriem Garfa-Traoré 3,  Florence Habarou 4,  Christine Bole-Feysot 2,  Patrick Nitschké 2,  Chris Ottolenghi 4,  Metodi D Metodiev 2,  Valérie Serre 5,  Isabelle Desguerre 6,  Nathalie Boddaert 7,  Olivier Hermine 1,  Arnold Munnich 7,  Agnès Rötig 8
Affiliations

Affiliations

  • 1 UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France; Laboratory of Excellence GR-Ex, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France.
  • 2 UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France.
  • 3 UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France; Plateau Technique de Cytométrie et d'Imagerie Cellulaires, Structure Fédérative de Recherche Necker, INSERM US 24, Centre National de la Recherche Scientifique, UMS 3633, 24 Boulevard du Montparnasse, 75015 Paris, France.
  • 4 UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France; Biochimie Métabolomique et Protéomique, Hôpital Necker - Enfants Malades, 149 Rue de Sèvres, 75015 Paris, France.
  • 5 UMR 7592, Université Paris Diderot and Institut Jacques Monod, Centre National de la Recherche Scientifique, 15 rue Hélène Brion, 75013 Paris, France.
  • 6 Departments of Pediatrics, Radiology, and Genetics, Hôpital Necker - Enfants Malades, 149 Rue de Sèvres, 75015 Paris, France.
  • 7 UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France; Departments of Pediatrics, Radiology, and Genetics, Hôpital Necker - Enfants Malades, 149 Rue de Sèvres, 75015 Paris, France.
  • 8 UMR 1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France; Laboratory of Excellence GR-Ex, Institut IMAGINE, 24 Boulevard du Montparnasse, 75015 Paris, France. Electronic address: [email protected].
PMID: 29395073 DOI: 10.1016/j.ajhg.2018.01.003
Abstract

Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous condition characterized by progressive dystonia with iron accumulation in the basal ganglia. How NBIA-associated mutations trigger iron overload remains poorly understood. After studying fibroblast cell lines from subjects carrying both known and unreported biallelic mutations in CRAT and REPS1, we ascribe iron overload to the abnormal recycling of Transferrin Receptor (TfR1) and the reduction of TfR1 palmitoylation in NBIA. Moreover, we describe palmitoylation as a hitherto unreported level of post-translational TfR1 regulation. A widely used antimalarial agent, artesunate, rescued abnormal TfR1 palmitoylation in cultured fibroblasts of NBIA subjects. These observations suggest therapeutic strategies aimed at targeting impaired TfR1 recycling and palmitoylation in NBIA.

Keywords

NBIA; artesunate; iron overload; mitochondria; neurodegeneration with brain iron accumulation; palmitoylation; transferrin receptor.

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